Ataractic use of dimethyl sulfoxide

ABSTRACT

EFFECTIVE AMOUNT OF DIMETHYL SULFOXIDE (DMSO), AS AN ESSENTIAL ACTIVE AGENT OR INGREDIENT, ARE ADMINISTERED TO ANIMALS TOPICALLY, BY INJECTION, BY INSTALLATION INTO BODY ORIFICES AND ORALLY FOR THE RELIEF OF SIGNS AND SYMPTOMS OF ANXIETY.

United States Patent O 3,790,682 ATARATIC USE OF DIMETHYL SULFOXIDERobert J. Herschler, Rte. 2, Box 1592, Camas, Wash., and Stanley W.Jacob, Oswego, reg.; said Jacob assignor to Crown ZellerbachCorporation, San Francisco, Calif.

No Drawing. Continuation-impart of application Ser. No. 686,295, Nov.28, 1967, now Patent No. 3,549,770, dated Dec. 22, 1970, which is acontinuation-in-part of applications Ser. Nos. 329,205, 329,208,329,209, 329,- 238 and 329,271, all Dec. 9, 1963, Ser. No. 346,366, Feb.10, 1964, and Ser. Nos. 417,781, 417,788 and 417,797, all Dec. 11, 1964,all now abandoned. This application Nov. 30, 1970, Ser. No. 93,841

Int. Cl. A61k 27/00 US. Cl. 424-337 3 Claims ABSTRACT OF THE DISCLOSUREEffective amounts of dimethyl sulfoxide (DMSO), as an essential activeagent or ingredient, are administered to animals topically, byinjection, by installation into body orifices and orally for the reliefof signs and symptoms of anxiety. I

CROSS REFERENCES TO RELATED APPLICATIONS This is a continuation-in-partof our copending United States application Ser. No. 686,295, entitledPharmaceutical Methods and Compositions with DMSO, filed Nov. 28, 1967,now U.S. Pat. No. 3,549,770, granted Dec. 22, 1970, which is, in turn, acontinuation-in-part of applications Ser. Nos. 329,238, entitledAnalgesia; 329,208, entitled Relief of Tissue Inflammation andStimulation of Repair; 329,205, entitled Relief of Signs and Symptoms ofArthritis; 329,271, entitled Relief of Signs and Symptoms of RespiratoryDistress; and 329,209, entitled Tranquilization, all filed Dec. 9, 1963;Ser. No. 346,366, entitled Control of Microorganisms, filed Feb. 10,1964; and Ser. Nos. 417,781, entitled Muscle Relaxation; 417,788,entitled Treatment of Burns and Promotion of Skin Grafts and 417,- 797,entitled Relieving Symptoms of Vascular Insufficiency," all filed Dec.11, 1964, all presently now abandoned, except for application Ser. No.686,295.

BACKGROUND OF THE INVENTION This invention relates to the use ofdimethyl sulfoxide as a pharmaceutical (i.e., as an essential activeagent or ingredient) to treat signs and symptoms of anxiety, as will bediscussed in detail herein.

For the various conditions treatable under the present invention, aconsiderable variety of medication and treatment exists. However, eachhas its limitations due to allergic response or potentially damagingside effects, restricted spectrum of activity (effective only in limitedtypes of disorders), restricted routes of administration, lack ofindividual response in a certain percentage of individuals, expense,etc. Therefore, additional agents are constantly being sought which canreplace, supplement or augment existing medication.

In achieving pharmaceutical effects, it is desirable to utilize an agentwhich is both well tolerated and conveniently administered. For itsobvious advantages of patient acceptability and convenience, topicalapplication is a particularly advantageous route. Relatively fewpharmaceuticals may be efiectively applied topically to the skin andmucous membranes of the body cavities, particularly to obtain a responsein disorders involving deeper tissues, structures and organs. Thus, withmost pharmaceuticals the only alternative to esthetically undesirableinjections has been through oral administration. Their usefulness hastherefore been restricted.

Accordingly, it is desirable in the field of medicine to provide newpharmaceuticals which are favorably tolerated and are substantiallynontoxic at effective levels of administration. It is further desirableto provide pharmaceuticals which may be administered conveniently and bya variety of routes, particularly topical.

The present invention has as a primary object to provide such a new,well-tolerated, substantially non-toxic pharmaceutical which iseffective for treatment of emotional overactivity and depression andwhich may be administered by a variety of routes, including topicalroute.

Dimethyl sulfoxide (DMSO), originally synthesized in 1866, is acolorless liquid at room temperature which melts at about 18.5 C. andboils at about C. Over the last 25 years it has been used increasinglyas an industrial solvent, reaction medium and chemical reactant and aconsiderable amount of literature has developed on its properties andindustrial uses. It has been investigated for toxicity in experimentalanimals and for several biological functions, namely, as a protectant infreeze pres ervation of living tissue and as a radio protectant inexperimental animals at high doses injected prior to radiation of theanimals. Uses have also been discovered by one of the present inventorsfor dimethyl sulfoxide in the agricultural field, namely, the enhancingpenetration of other agents into plants, in controlling plant virus andin stimulating plant metabolic functions.

Copending applications have also been filed by one of the applicantshereof concerning other discovered pharmaceutical properties of dimethylsulfoxide and relating to enhancing animal tissue penetration ofphysiologically active agents with dimethyl sulfoxide. These includeapplication Ser. No. 753,231, filed Aug. 16, 1968, and twocontemporaneously filed applications entitled Enhancing TissuePenetration of Physiologically Active Steroids with DMSO andPharmaceutical compositions of DMSO with Physiologically Active Agents,respectively.

SUMMARY OF THE INVENTION Quite surprisingly, in the light of the longhistory, extensive experimentation, study and evaluation of thiscompound, it has now been discovered that dimethyl sulfoxide (DMSO) haspreviously unrecognized valuable and extensive pharmaceutical activity.In applicants copending parent application Ser. No. 686,295 is discloseda number of such discovered activities, including activities as anantiinflammatory agent, analgesic muscle relaxant, tissue repair agentand agent for relieving vascular insufliciency. The present applicationis directed to another discovered activity, namely, the use of DMSO totreat signs and symptoms of anxiety. Dimethyl sulfoxide is rapidlyrendered systemic in the body from all normal routes of administrationand, importantly, also that it may be applied topically to the intactskin or mucous membrane to achieve highly unusual rapid absorption forsystemic elfect.

GENERAL DESCRIPTION OF THE INVENTION The phenomenon of ataraxis ortranquilization is the relief of the higher neural centers of anorganism from the disordering eifects of anxiety, such as tension, lossof emotional control and equilibrium, depression, anergy and like signsand symptoms. Anxiety may be the result of traumatic events, such asphysical injury, pain, fear and frustration, and it is a common factorin most mental diseases, including neurotic and psychotic states. Arecognized class of drugs has been developed, including the widely usedchlorpromazine and the meprobamates for treating organisms sufferingfrom the manifestations of anxiety. These drugs are characterized byreducing the overactivity or lessening emotional excesses and anxietytensions and the like and by exerting an antidepressant effect onanergic individuals, particularly in neurotic and psychotic disorders.It is a characteristic of these drugs that they attain in desirableproperties without unduly depressing the central nervous system or theconsciousness or alertness of the subject. This class of drugs hasfrequently been referred to as tranquilizers, or ataraxics.

In addition to its well-known employment in human medication, includingclinical and sub-clinical psychiatric and psychotherapeutic treatment,ataractic medication has become well established in veterinary andrelated medical practice. In common veterinary experience, animals ofmany kinds may become excited, with harmful results to themselves andtheir handlers by the occurrence of anxietyproducing events, such asmedical procedures, handling, exposure to unfamiliar surroundings, etc.Ataractic agents are usefully employed in managing veterinary animals,for example, dogs, horses, cats, etc., under such circumstances.

Similarly, dimethyl sulfoxide has a tranquilizing or ataractic effect inthe same sense of alleviating the signs and symptoms of anxiety. Theparticular amount of dimethyl sulfoxide to be administered to alleviatethe manifestations of anxiety will understandably be determined by theexpertise of the attending practitioner who considers the nature andseverity of the manifestations, the response desired or observed, andthe subject. A great degree of emotional overactivity or depression willnormally urge the practitioner to administer higher concentrations ofdimethyl sulfoxide in greater amounts, more repeatedly, say, an amountto obtain a daily dosage of 15 to 20 cc. of dimethyl sulfoxide. Aneffect, however, may often be obtained by only one or two treatments ofonly a few oc.s of dimethyl sulfoxide compositions containing anywherefrom about 25% to 100% of the compound.

Dimethyl sulfoxide may be administered by the usual oral and injectableroutes, and it may be applied topically to a cutaneous region or to themucous membranes of the various body cavities as by direct applicationor instillation. This may be done by applying a small volume such as 2to 5 cc. of a composition containing at least about 50% dimethylsulfoxide and repeating the dosage as necessary.

Generally, as illustrated by the examples which follow, the dosage maybe as low as 0.01 gram per kilogram body weight and the optimum amountanywhere from around 0.02 to 0.05 up to 1.0 gram per kilogram of bodyweight per day or somewhat higher in a few instances. The averageindividual dose may be in the neighborhood of 0.1 to 0.2 gram per kg.*body weight. However, the optimum dose will depend to a considerableextent upon the type and extent of the disorder and the mode ofapplication.

The treatment may be repeated once or twice daily, or even morefrequently, until appropriate response is obtained or for the durationof the complaint. For some indications (such as many acute situations),only one or two applications involving a few cc.s of dimethyl sulfoxidemay be necessary, while in chronic situations a more sustained regimenfor a prolonged period or follow-up treatments may be called for. In anycase, the optimum amount for a given disorder will depend upon thefactors previously mentioned.

Topical application to cutaneous regions such as the skin and mucousmembranes will lead to absorption so the vascular system will carry thecompound to the central nervous system where the tranquilizing effectwill occur. It is a unique advantage that dimethyl sulfoxide penetratesor is absorbed in a surprising manner through the cutaneous regions.Although the topical route may be preferred, local injections may alsobe employed and preferably lower concentrations of 1% to 20% dimethylsulfoxide are used for this purpose.

Topical application to a surface area rich in blood vessels (as, forexample, on the chest, back, legs and arms) is quite convenient. Higherconcentrations are preferred for topical applications, such as at least25% and, more often, at least about 50%. The dimethyl sulfoxidecomposition may be applied by means of a cotton swab or other softapplicator. It may be conveniently applied in the form of a spray bymeans of an aerosol bomb or an atomizer or in a thickening base, etc.Desirably, at each application the surface treated is thoroughly wetted.Where large areas are to be treated, it may be desirable to immerse anentire limb, torso, or body into a dilute aqueous solution of dimethylsulfoxide. At the lower concentrations greater volumes of dimethylsulfoxide solutions may be administered more frequently as with bathingsolutions for some purposes. Less frequent applications may beeffectively made with solutions containing at least about 50% ofdimethyl sulfoxide.

Composition and dosage forms include undiluted dimethly sulfoxide or,more preferably, dimethyl sulfoxide along with appropriatepharmaceutical diluents, excipients or adjuvants. In general,concentrations of dimethyl sulfoxide may vary from 1% to For topicaluse, however, higher concentrations of from 10% to 25% and above forapplication to mucous membranes and at least about 50% for dermalapplication are preferred. For more information on dosages, compositionforms and routes of administration, reference is made to copendingapplication Ser. No. 686,295, the disclosure of which is incorporatedherein by reference.

The following example is illustrative:

Example The effective anti-anxiety activity of DMSO may be evidenced bythe standard testing techniques which have been utilized for assessingsuch activity. One of the most prominent of such tests is that developedby Geller and Seifter utilizing a conflict situation or discriminatedpunishment schedule, as described in their articles Effects ofMono-Urethans, Diurethans and Barbiturates on Punishment Discrimination,J. Pharmacol. & Exper. Therap. 136:284, 1962; and Elfects ofChlordiazepoxide and Chlorpromazine on Punishment Discrimination,"Psychopharmacologia 3:374, 1962.

A test model was set up as described in the latter mentioned articleutilizing a Skinner box and associated programming equipment. A flashinglight stimulus was utilized in place of an auditory stimulus.

Twelve male albino rats of Holtzman Sprague Dawley strain approximatelyeight weeks old at the start of the experiment were used. The rats weretrained to press a lever in the Skinner box for a milk reward. When thelever-pressing rats had stabilized at an average of one reward every twominutes, a flashing light stimulus of three minutes duration wasintroduced at fifteen-minute intervals, together with a punishmentcontingency so that all lever responses during the light stimulus notonly produced the liquid food reward but also an electric shock to theanimals feet.

The animals were observed to respond infrequently during the conflictperiod, that is, they did not choose to press the lever for a foodreward while subjected to the flashing light stimulus.

To each of six of the rats 1 gram per kg. of body weight of DMSO wasthen administered by intraperitoneal injection of an isotonic salinesolution containing 25% by Weight of DMSO. Within one hour theDMSO-treated rats were seen to respond with twice the frequency of leverpresses during the conflict periods, as compared to the control group ofrats. This increased rate of response endured for four hours. Theanimals in both the test group and the control group maintained a steadyrate of re spouse of an average of one reward every two minutes. Thetest was replicated by again administering DMSO in the same dosage tothe test group of rats and the same results were observed.

The foregoing invention can now be practiced by those skilled in theart. Such skilled persons will know that the invention is notnecessarily restricted to the particular embodiments presented herein.The scope of the invention is to be defined by the terms of thefollowing claims, as given meaning by the preceding description.

We claim:

1. A method of relieving signs and symptoms of anxiety in a mammaliansubject suflering therefrom which comprises administering to the mammala nontoxic amount of dimethyl sulfoxide effective to relieve signs andsymptoms of anxiety.

2. -A method as in claim 1 and wherein the amount of dimethyl sulfoxideadministered is between about 0.01 and 1 gram per kg. of body weight perday.

3. A method as in claim 2 and wherein said dimethyl sulfoxide isadministered to said subject topically to the intact skin in acomposition containing at least 50% by weight of dimethyl sulfoxide.

References Cited UNITED STATES PATENTS 3,549,770 12/1970 Herschler etal. 424337 3,551,554 12/1970 Herschler 4247 OTHER REFERENCES Uramura(Igaku Kenkyu 2235-61 (1961), English translation, 16 pp. AnExperimental Study on the Toxicity of Dimethyl Sulfoxide Used as aSolvent.

Brown et al., J. Pharm. & Pharmacol. 15: 688-692, October 1963, A Noteon the Toxicity and Solvent Properties of Dimethyl Sulfoxide."

Ferm Lancet, I an. 22, 1966, pp. 208-209, Teratogenic Effect of DimethylSulfoxide Ramirez et al. Ann. New York Acad. Sci. 141 Art 1.:655-667,Mar. 15, 1967, Dimethyl Sulfoxide in the Treatment of Mental Patients.

SHEP K. ROSE, Primary Examiner

